The goal of this project is to use magnetic resonance imaging (MRI) to better define the natural history of multiple sclerosis (MS) and to identify potentially effective therapies. These studies employ a variety of imaging techniques, including fast-spin echo images, gadolinium-DTPA enhanced images, fluid-attenuated inversion recovery imaging (FLAIR), and magnetization transfer imaging. It is also expected that the use of MRI to monitor new therapies may provide additional insight into the stage of lesion development targeted by the therapy. Recent results indicate that in a cohort of patients with early relapsing-remitting MS, nearly two-thirds will have evidence of new disease activity as measured by contrast-enhancing lesions over a three-month period indicating that in most patients MS is an active disease even during the early states. Furthermore, serial analysis of lesion load seen on T2-weighted images indicate that considerable fluctuation occurs from month to month but again progression is seen. The serial imaging data obtained from the natural history portion of this study have been used to define the sample size requirements for trials using MRI as an outcome measure. Trials using MRI as a primary outcome measure can provide rapid preliminary evaluation of the effect of new therapies. Studies of the effect of interferon beta-1b using a baseline, versus treatment design, indicate that a dramatic reduction in new lesion activity can be shown in a sample as small as 12 patients followed six months prior to treatment and crossed over to six months of treatment. Enlargement of this cohort to 33 patients followed for approximately two years has allowed a detailed analysis of the effect of neutralizing antibody of treatment effect with beta-interferon. Eleven of the 33 patients developed antibody, and in 6 of these patients, antibody resolved spontaneously. Of the 11 antibody-positive patients, only 5 had significant reductions in treatment effect. Thus, MRI provides a powerful tool for assessing the potential of new therapies in MS.